Cocaine and nicotine abuse remain serious problems in today's society, and despite new treatments, recidivism rates remain high. While it is generally agreed that the powerful reinforcing and, in the case of cocaine, euphorigenic properties, are principally responsible for maintaining drug-seeking and drug-taking behavior, little is known about the neurobiological mechanisms and sites of action of these agents in the human central nervous system (CNS). Such knowledge appears necessary for the ultimate development of more successful treatment strategies. As such, the overall goal of this project is to define those neuronal systems and circuits mediating nicotine and cocaine actions in the human CNS and to determine which subset of these sites participate in their withdrawal, craving and reinforcing properties. As pharmacological agents, cocaine and nicotine produce a number of profound behavioral and physiological effects. Evidence from animal models support their interaction with the mesocorticolimbic (MCL) dopamine system in producing their reinforcing properties. However, both the role of the MCL system and where and how these drugs act in humans is almost completely unknown as the tools to noninvasively address this question have lacked the necessary sensitivity. Finally, it is recognized that drugs do not exert a simple pharmacological action within CNS. Their powerful stimulant properties become paired with environmental cues to form conditioned responses (CRs) which are thought to be able to promote continued drug use and increase relapse probability. Once again, virtually nothing is known regarding their neuroanatomic substrates. It is hypothesized that these agents activate cortical and subcortical terminal fields of the MCLDA system and that these regions will also be selectively altered during chronic drug use as manifest by alterations in system functioning during drug withdrawal and craving. With the relationship between cerebral electrochemical activity, blood flow and glucose metabolism, functional metabolic mapping of the nervous system is possible using a number of noninvasive techniques in man. Functional magnetic resonance imaging is a very new application of MRI that permits an examination of functional cerebral activity without the use of X-rays or ionizing radiation. Its excellent temporal (seconds) and spatial (2-3 mm) resolution permits virtual 'real time' imaging and within subject designs not possible with other current procedures. This proposal will utilize this novel technique to determine the neuroanatomic sites of action of nicotine and cocaine and the ability of these drugs to alter neuronal responsivity when performing cognitive tasks believed to activate neuronal DA terminal regions. We will also examine the time course of withdrawal and the effects of cue-induced craving on both "resting" and task-induced neuronal activation. We will also address the question of reinforcement circuitry in the human brain. It is hoped that these data may eventually lead to better understanding of, and strategies for treating drug addiction, producing, in turn, a decrease in recidivism.